2-hydroxymethylolanzapine compositions and methods

ABSTRACT

Methods and compositions are disclosed utilizing 2-hydroxymethylolanzapine for the treatment of psychosis in humans. 2-Hydroxymethylolanzapine exhibits a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine. 2-Hydroxymethylolanzapine is also useful for the treatment of acute mania, mild anxiety states, anxiety disorders, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autistic disorder, excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis.

FIELD OF THE INVENTION

The invention relates to methods of treating psychosis, acute mania,mild anxiety states, schizophrenia, bipolar disorder, autistic disorder,excessive aggression, substance abuse, depressive signs and symptoms,tic disorder, functional bowel disorder and fungal dermatitis.

BACKGROUND OF THE INVENTION

Olanzapine I is an orally active, potent, antipsychotic agent.

It is commercially available as Zyprexa® from Eli Lilly Co. Theantipsychotic effect of olanzapine is ascribed by the literature toblocking of the dopamine D₂ receptor and to 5-HT antagonism.

One of the main serum metabolites of olanzapine is2-hydroxymethylolanzapine II, formed by oxidation of the methyl group atthe 2-position of the thiophene ring. The chemical name of II is4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin-2-methanol andhereinafter is referred to as 2-hydroxymethylolanzapine.

Formation of 2-hydroxymethylolanzapine occurs in the liver through theenzymes of the P450 system. 2-Hydroxymethylolanzapine is formed bycytochrome P450 2D6 (CYP2D6). CYP2D6 is polymorphically expressed in thehuman population. The mutant allele constitutes the recessive trait.Homozygous carriers of the mutation completely lack CYP2D6 and arereferred to as poor metabolizers; persons homozygous and heterozygousfor the “normal” allele are extensive metabolizers. In addition toproblems arising from variability in dosage regimens, the clinical useof CYP2D6-metabolized drugs and of CYP2D6 inhibitors, which includes avariety of antiarrhythmic agents, beta-adrenoceptor blockers andtricyclic antidepressants, in conjunction with olanzapine, may inhibitolanzapine metabolism.

It is therefore desirable to find a compound with the advantages ofolanzapine which would provide a more predictable dosage regimen in thepatient population and that would decrease the chances for drug-druginteraction.

SUMMARY OF THE INVENTION

The present invention relates to use of 2-hydroxymethylolanzapine fortreating psychosis, acute mania, mild anxiety states, anxiety disorders,schizophrenia, bipolar disorder, autistic disorder, attention deficithyperactivity disorder (“ADHD”), excessive aggression, substance abuse,depressive signs and symptoms, tic disorder, functional bowel disorderand fungal dermatitis. It provides this effective treatment whileexhibiting fewer or less severe adverse effects than olanzapine, alessened liability toward drug-drug interactions than olanzapine and amore predictable dosing regimen than olanzapine.

The invention also relates to pharmaceutical compositions comprising2-hydroxymethylolanzapine. In one embodiment said pharmaceuticalcompositions comprise solid unit dosage forms, such as tablets orcapsules containing 2-hydroxymethylolanzapine.

DETAILED DESCRIPTION OF THE INVENTION

The active compound of the compositions and methods of the presentinvention is 2-hydroxymethylolanzapine. It may be prepared as describedby Calligaro et al., [Biorg. & Med. Chem. Letters, 1, 25-30, (1997)],the disclosure of which is incorporated herein by reference. Calligaroconcludes that the “data demonstrate that all metabolites aresignificantly less active than olanzapine. It is therefore unlikely thatthe activity of these agents contributes to the overall pharmacologicalprofile of the parent compound.” Galatsis [Annual Reports in MedicinalChemistry 32, 313, (1997)] also states that olanzapine's “ten metabolicproducts are inactive.” Kando et al. [The Annals of Pharmacotherapy, 31,1325-1334, (1997)] report that the metabolites “lack antipsychoticactivity at the concentrations that have been observed.”

It has now been discovered that 2-hydroxymethylolanzapine is a superioragent for treating psychoses such as acute mania and schizophrenia, mildanxiety states, anxiety disorders, bipolar disorder, autistic disorder,attention deficit hyperactivity disorder, excessive aggression,substance abuse, depressive signs and symptoms, tic disorder, functionalbowel disorder and fungal dermatitis. In particular, the methods andcompositions of the present invention may be used to treat humanssuffering from such conditions. 2-Hydroxymethylolanzapine provides thiseffective treatment while exhibiting fewer or less severe adverseeffects than olanzapine, a lessened liability toward drug-druginteractions than olanzapine and a more predictable dosing regimen thanolanzapine.

Adverse effects of olanzapine include postural hypotension,constipation, dry mouth, weight gain, dizziness, fast heartbeat,personality disorder and akathisia. Other side effects of olanzapineinclude tacycardia, irregular pulse, diaphoresis, cardiac dysrhythmia,flu syndrome, nausea, vomiting, hematuria, metrorrhagia, urinaryincontinence, abdominal pain, premenstrual syndrome, somnolence,agitation, insomnia, nervousness, headache, dyspnea, tremors,myoglobinuria (rhabdomyolysis), drug-induced Parkinsonism, amblyopia andasthenia.

The present invention encompasses a method of treating psychosis whichcomprises administering to a human in need of such therapy, an amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof,said amount being sufficient to alleviate the symptoms of the psychoticcondition. Psychotic conditions of particular interest in humansinclude, but are not limited to, ADHD, schizophrenia and acute mania.

The present invention also encompasses an oral composition whichcomprises a pharmaceutically acceptable carrier for oral administrationand a therapeutically effective amount of 2-hydroxymethylolanzapine or apharmaceutically acceptable salt thereof. Preferably the composition isin the form of a tablet or capsule, and the amount of2-hydroxymethylolanzapine in the tablet or capsule is preferably about 1to 150 mg.

A pharmaceutical composition of the present invention may also contain atherapeutically effective amount of a selective serotonin reuptakeinhibitor in addition to a therapeutically effective amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier for oral administration.Selective serotonin reuptake inhibitors include, but are not limited toparoxetine (PAXIL®), fluoxetine (PROZAC®), sertaline (ZOLOFT®),fluvoxamine (LUVOX®), venlafaxine (EFFEXOR®), and nefazodone (SERZONE®),as well as any optically pure isomers or metabolites of any of thesecompounds.

The present invention further encompasses a method of treating bipolardisorder, anxiety disorder, tic disorder, autistic disorder, excessiveaggression, ADHD, substance abuse, and signs and symptoms of depressionand of treating conditions caused by or contributed to by any of these.The method comprises administering to a human in need of such therapy,an amount of 2-hydroxy-methylolanzapine or a pharmaceutically acceptablesalt thereof, said amount being sufficient to alleviate the symptoms ofthe particular condition.

The present invention further encompasses a method of treating fungaldermatitis and functional bowel disorder. The method comprisesadministering to a human in need of such therapy, an amount of2-hydroxy-methylolanzapine or a pharmaceutically acceptable saltthereof, said amount being sufficient to alleviate the symptoms of theparticular condition.

Utilizing 2-hydroxymethylolanzapine results in enhanced dosagepredictability and an improved therapeutic index. In particular,2-hydroxymethylolanzapine exhibits less variation in the patientpopulation between so-called extensive metabolizers and poormetabolizers than does olanzapine. 2-Hydroxymethylolanzapine may also beused to treat various conditions or disorders while minimizing oravoiding adverse cardiac events associated with administration ofolanzopine. Furthermore, 2-hydroxymethylolanzapine can be administeredto treat various conditions or disorders while minimizing or avoidingany impact on hepatic function (e.g., liver enzyme abnormalities).

The term “psychotic condition” as used herein means pathologicpsychological conditions which are psychoses or may be associated withpsychotic features. Such conditions include, but are not limited to thepsychotic disorders which have been characterized in the DSM-IV-R,Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed.(1994), including schizophrenia and acute mania. The DSM-IV-R wasprepared by the Task Force on Nomenclature and Statistics of theAmerican Association, and provides clear descriptions of diagnosticcategories. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forpathologic psychological conditions and that these systems evolve withmedical scientific progress.

The term “bipolar disorder” as used herein refers to a conditioncharacterized as a Bipolar disorder, in the DSM-IV-R as category 296.xx,including both Bipolar Disorder I and Bipolar Disorder II.

The term “autistic disorder” as used herein means a conditioncharacterized as an Autistic Disorder in the DSM-IV-R as category299.xx, including 299.00, 299.80, and 299.10, preferably 299.00.

The term “anxiety disorders” includes, but is not limited toobsessive-compulsive disorder, psychoactive substance anxiety disorder,post-traumatic stress disorder, generalized anxiety disorder, anxietydisorder NOS, and organic anxiety disorder.

The term “substance abuse” as used herein means the undesired physicaland/or psychological dependence on a drug. The term refers to dependenceon a substance such as cocaine, psychedelic agents, marijuana,amphetamines, hallucinogen, phencyclidine, benzodiazepines, alcohol andnicotine.

The term “attention deficit hyperactivity disorder” and “ADHD” as usedherein mean a condition or disorder characterized by a persistentpattern of inattention, hyperactivity, impulsivity, or any combinationthereof.

The term “excessive aggression” as used herein refers to a conditioncharacterized by aggression that is so excessive that it interferes withthe individual's daily functions, relationships, and may threaten thesafety of the individual, for example in a situation in which violentsuicide is contemplated. The excessive aggression which may be treatedusing the method claimed herein is independent of a psychotic conditionand not directly related to the consumption of a drug or othersubstance.

A tic is a sudden, rapid recurrent, nonrhythmic, stereotyped motormovement or vocalization, experienced as irresistible but suppressiblefor varying lengths of time. Common simple motor tics include eyeblinking, neck jerking, shoulder shrugging, facial grimacing, andcoughing. Common simple vocal tics include throat clearing, grunting,sniffing, snorting, and barking. Common complex motor tics includefacial gestures, grooming behaviors, jumping, touching, stamping, andsmelling an object. Common complex vocal tics include repeating words orphrases out of context, coprolalia (use of socially unacceptable words,frequently obscene) palilalia (repeating one's own sounds or words), andecholalia(repeating the last heard sound, word or phrase). The term “ticdisorder” as used herein means includes tic disorders featuring one ormore motor tics and one or more tic and more vocal tics, and vocal tics.Examples include Transient Tic Disorder, Tourette's Disorder, ChronicVocal Tic Disorder, and Tic Disorder not otherwise specified asdescribed by DSM-IV-R.

The term “functional bowel disorder” refers to a functionalgastrointestinal disorder manifested by (1) abdominal pain or (2)symptoms of disturbed defecation (urgency, straining, feeling ofincomplete evacuation, altered stool form [consistency] and alteredbowel frequency/timing) or (3) bloating (distension) or any combinationthereof. The term “functional bowel disorder” includes but is notlimited to irritable bowel syndrome, hypermotility, ichlasia, hypertoniclower esophogeal sphinchter, tachygastria, constipation, andhypermotility associated with irritable bowel syndrome.

The term “treating” as used herein includes prophylaxis of the namedcondition or amelioration or elimination of the condition once it hasbeen established.

The magnitude of a prophylactic or therapeutic dose of2-hydroxymethylolanzapine in the acute or chronic management of diseasewill vary with the severity of the condition to be treated and the routeof administration. The dose and perhaps the dose frequency will alsovary according to the age, body weight and response of the individualpatient. In general, the total daily dose range for2-hydroxymethylolanzapine for the conditions described herein is fromabout 1 to 150 mg in single or divided doses. In managing the patient,the therapy should be initiated at a lower dose, perhaps at about 1 mgand increased up to a desired dose depending on the patient's globalresponse. It is further recommended that children and patients over 65years and those with impaired renal or hepatic function, initiallyreceive low doses, and that they be titrated based on individualresponse(s) and blood level(s). It may be necessary to use dosagesoutside these ranges in some cases as will be apparent to those skilledin the art. Further, it is noted that the clinician or treatingphysician will know how and when to interrupt, adjust, or terminatetherapy in conjunction with individual patient response.

The relative activity, potency and specificity of2-hydroxymethylolanzapine can determined by a pharmacological study inanimals according to the method of Nyberg et al. [Psychopharmacology119, 345-348 (1995)]. The test provides an estimate of relativeactivity, potency and, through a measure of specificity, an estimate oftherapeutic index. Other animal studies which may be used include, butare not limited to, studies involving conditioned avoidance, apomorphineinduced climbing and blockade of 5-hydroxytryptophan-induced headtwitching. Although the differential metabolism among patientpopulations can be determined by a clinical study in humans, lessexpensive and time-consuming substitutes are provided by the methods ofKerr et al. [Biochem. Pharmacol. 47, 1969-1979 (1994)] and Karam et al.[Drug Metab. Dispos. 24, 1081-1087 (1996)]. Similarly, the potential fordrug-drug interactions may be assessed clinically according to themethods of Leach et al. [Epilepsia 37, 1100-1106 (1996)] or in vitroaccording to the methods of Kerr et al. [op. cit.] and Turner and Renton[Can. J. Physiol. Pharmacol. 67, 582-586 (1989)]. In addition, therelative activity, potency and specificity of 2-hydroxymethylolanzapinemay be tested using various in vitro receptor assays, including but notlimited to assays involving dopamine receptors, serotonin receptors,adrenergic receptors, and muscarinic receptors.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of 2-hydroxymethylolanzapine. Rectal,oral, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration are possible, but oraladministration is preferred. Oral dosage forms include tablets, troches,dispersions, suspensions, solutions, capsules, soft elastic gelatincapsules, and the like.

The pharmaceutical compositions of the present invention comprise2-hydroxymethylolanzapine as the active ingredient, or apharmaceutically acceptable salt thereof, and may also contain apharmaceutically acceptable carrier, and optionally, other therapeuticingredients. In a preferred embodiment, pharmaceutical compositions ofthe present invention comprise 2-hydroxymethylolanzapine in combinationwith a selective serotonin reuptake inhibitor.

The terms “pharmaceutically acceptable salts” or “a pharmaceuticallyacceptable salt thereof” refer to salts prepared from pharmaceuticallyacceptable non-toxic acids. Since the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids including inorganic and organic acids. Suitablepharmaceutically acceptable acid addition salts for the compound of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic (mesylate), mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and thelike.

The compositions of the present invention include suspensions,solutions, elixirs or solid dosage forms. Carriers such as starches,sugars, and microcrystalline cellulose, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like are suitable inthe case of oral solid preparations (such as powders, capsules, andtablets), and oral solid preparations are preferred over the oral liquidpreparations. Oral dosage forms suitable for 2-hydroxymethylolanzapineare described in U.S. Pat. Nos. 5, 229,382 and 5,605,897 and in PCTapplication WO97/11700, the disclosures of which are incorporated hereinby reference.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releaseformulations, which are well known in the art. Compositions suitable forrectal administration are described in European Application 645140, thedisclosure of which is incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, each containing a predetermined amount of theactive ingredient, as a powder or granules, or as a solution or asuspension in an aqueous liquid, a non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such compositions may beprepared by any of the methods of pharmacy, but all methods include thestep of bringing into association the active ingredient with the carrierwhich constitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active agent ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet or capsule contains about 1 mg toabout 150 mg of the active ingredient.

An enteric coating, such as the polyacrylate Eudragit L® and Eudragit S®series, is applied, preferably with an aqueous dispersion of the coatingpolymer. Tablets of other strengths may be prepared by altering theratio of active ingredient to the excipients or to the final weight ofthe tablet.

In another embodiment, pharmaceutical compositions of the presentinvention suitable for oral administration may be formulated in a softelastic gelatin capsule unit dosage form using conventional methods(see, e.g., Ebert, Pharm. Tech., 1(5):44-50 (1977). Soft elastic gelatincapsules have a soft, globular, gelatin shell somewhat thicker than thatof hard gelatin capsules, wherein a gelatin is plasticized by theaddition of glycerine, sorbitol, or a similar polyol. The hardness ofthe capsule shell may be changed by varying the type of gelatin and theamounts of plasticizer and water. The soft gelatin shells may contain apreservative to prevent the growth of fungi, such as methyl-andpropylparabens and sorbic acid. The active ingredient may be dissolvedor suspended in a suitable liquid vehicle or carrier, such as vegetableor mineral oils, glycols such as poly ethylene glycol and propyleneglycol, triglycerides, surfactants such as polysorbates, or acombination thereof.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compositions of the presentinvention, as well as their utility. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the invention.

EXAMPLES

Example 1 - 20 mg Tablets Composition per tablet:2-hydroxymethylolanzapine  20 mg croscarmellose  60 mg colloidal silicondioxide  8 mg magnesium stearate  1 mg microcrystalline cellulose 190 mgcroscarmellose  15 mg talc  10 mg Total 304 mg

Example 1

2-Hydroxymethylolanzapine and silicon dioxide are dry mixed, the firstportion of croscarmellose is added and the mixture is further dry mixed.The magnesium stearate is added, dry mixed and the mixture is runthrough a roller compactor and mill. The resulting dry granulate ismixed with the remaining three ingredients and compressed into tablets.

Example 2 - 10 mg Tablets Composition per unit dosage:2-hydroxymethylolanzapine 10 mg pregelatinized starch 200 mgmicrocrystalline cellulose 25 mg povidone 15 mg croscarmellose 10 mgmagnesium stearate 3.75 mg FD&C yellow #2 lake 2.5 mg Water (5 mL) Total266.25 mg

Example 2

The ingredients above are mixed well in the proportions shown in a highshear mixer until uniform granules result. The mixture is tray-dried at40° C. under vacuum until the desired consistency is reached. Thegranules are milled to less than 60 mesh using a screen mill andcompressed into tablets.

What is claimed is:
 1. A method of treating psychosis which comprisesadministering to a human a therapeutically effective amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof.2. The method according to claim 1, wherein schizophrenia is treated. 3.The method according to claim 1, wherein acute mania is treated.
 4. Amethod of treating mild anxiety states which comprises administering toa human a therapeutically effective amount of 2-hydroxymethylolanzapineor a pharmaceutically acceptable salt thereof.
 5. A method of treatingbipolar disorder which comprises administering to a human atherapeutically effective amount of 2-hydroxymethylolanzapine or apharmaceutically acceptable salt thereof.
 6. A method of treatingautistic disorder which comprises administering to a human atherapeutically effective amount of 2-hydroxymethylolanzapine or apharmaceutically acceptable salt thereof.
 7. A method of treatingattention deficit hyperactivity disorder which comprises administeringto a human a therapeutically effective amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof.8. A method of treating excessive aggression which comprisesadministering to a human a therapeutically effective amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof.9. A method of treating substance abuse which comprises administering toa human a therapeutically effective amount of 2-hydroxymethylolanzapineor a pharmaceutically acceptable salt thereof.
 10. A method of treatingdepressive signs and symptoms which comprises administering to a human atherapeutically effective amount of 2-hydroxymethylolanzapine or apharmaceutically acceptable salt thereof.
 11. A method of treating ticdisorder which comprises administering to a human a therapeuticallyeffective amount of 2-hydroxymethylolanzapine or a pharmaceuticallyacceptable salt thereof.
 12. A method of treating functional boweldisorder which comprises administering to a human a therapeuticallyeffective amount of 2-hydroxymethylolanzapine or a pharmaceuticallyacceptable salt thereof.
 13. A method of treating fungal dermatitiswhich comprises administering to a human a therapeutically effectiveamount of 2-hydroxymethylolanzapine or a pharmaceutically acceptablesalt thereof.
 14. A method of treating anxiety disorder which comprisesadministering to a human a therapeutically effective amount of2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof.15. The method according to claim 14, wherein the anxiety disorder isselected from the group consisting of obsessive-compulsive disorder,post-traumatic stress disorder, psychoactive substance disorder,generalized anxiety disorder, organic anxiety disorder, and anxietydisorder NOS.
 16. The method of any of claim 1 wherein2-hydroxymethylolanzapine is administered orally.
 17. The method ofclaim 16 wherein the amount of 2-hydroxymethylolanzapine or apharmaceutically acceptable salt thereof administered is from about 1 mgto about 150 mg per day.
 18. The method of any of claim 1 wherein2-hydroxymethylolanzapine is administered in combination with atherapeutically effective amount of a selective serotonin reuptakeinhibitor.
 19. The method of any of claim 1 wherein2-hydroxymethylolanzapine is administered in combination with a drugchosen from paroxetine, fluoxetine, sertaline, fluvoxamine, venlafaxineand nefazodone.
 20. A pharmaceutical composition two-hydroxy methylolanzapine or pharmaceutically acceptable salt and a carrier,additionally comprising a therapeutically effective amount of aselective serotonin reuptake inhibitor compound or a pharmaceuticallyacceptable salt thereof.
 21. A pharmaceutical composition two-hydroxymethyl olanzapine or pharmaceutically acceptable salt and a carrier,additionally comprising a therapeutically effective amount of a drugchosen from paroxetine, fluoxetine, sertaline, fluvoxamine, venlafaxineand nefazodone.